Targeted Immune and Growth Factor Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension Reveals a Potential Role of the Hepatic Growth Factor

Abstract

Although inflammatory features have been reported in the pressure-overloaded right ventricle, prior proteomic studies of pulmonary arterial hypertension (PAH) have mainly focused on identifying circulating biomarkers associated with pulmonary vascular disease severity or outcomes. This study sought to determine the circulating proteomic immune profile associated with right heart maladaptive phenotype (RHMP) in PAH. In this observational study of PAH patients enrolled at Stanford University from 2008-2011 (n=121, discovery cohort) and from 2011-2014 (n=76, validation cohort), we carried out plasma proteomic profiling using Luminex® multiplex immunoassay (48-plex of interleukins, chemokines and growth factors). RHMP was defined by the Mayo right heart score (based on echocardiographic right ventricular RV strain, NYHA class and NT-proBNP) and Stanford right heart score (based on RV end-systolic remodeling index, NYHA class and NT-proBNP). The association between cytokines and RHMP was assessed by partial least square regression (PLS-R). To further validate the circulating markers associated with RHMP, we confirmed tissue-level expression in RV biopsies from PAH patients. Median age was 50 [39-59] years in the discovery cohort, where the majority of patients was female (74%) and PAH was most commonly associated with connective tissue disease (33%). Patients from the validation cohort had more severe features (lower six minute walk test distance, lower cardiac index and higher levels of NT-proBNP) than patients from the discovery cohort, with similar resistance levels and right heart echocardiography metrics. High levels of hepatic growth factor (HGF), stem cell growth factor beta (SCGFβ), nerve growth factor (NGF) and SDF1 were significantly associated with worst Mayo and Stanford scores but not with pulmonary vascular resistance or mean pulmonary arterial pressure, in both cohorts. In the right ventricle of deceased PAH patients, we confirmed expression of HGF and its receptor cMet using immunofluorescence. High plasma levels of HGF, SCGFβ, NGF and SDF1 are associated with RHMP in PAH, independent of pulmonary vascular disease severity. The HGF-cMet pathway warrants further exploration to investigate a potential RV specific therapeutic target.